Elsevier

Life Sciences

Volume 45, Issue 18, 1989, Pages 1627-1636
Life Sciences

Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model

https://doi.org/10.1016/0024-3205(89)90272-5Get rights and content

Abstract

To determine whether the differences in development of acute tolerance to several morphine actions correlate with the mu receptor subtype mediating them, we have examined the appearance of acute tolerance to analgesia, respiratory depression, gastrointestinal transit, and hormone release in an intravenous morphine infusion model. Analgesia, a naloxonazine-sensitive mu1 action, peaked at 2 hr after initiation of the infusions. The log dose-response relationship of the infusion rate to peak tailflick latency was linear from 10 to 50 μg/kg/min. By 8 hr, the tailflick latencies declined nearly to baseline levels, implying the rapid development of tolerance. Tolerance to morphine-induced prolactin release, another mu1 action, also developed rapidly over 8 hr. In contrast, two mu2 actions, respiratory depression measured with arterial blood gas determinations and gastrointestinal transit, showed no significant tolerance over a similar 8 hr infusion. We also observed no tolerance to morphine-induced growth hormone release, a non-mu1 action, over the same period. Thus, these results demonstrate that mu1 actions develop tolerance in an infusion model far more rapidly than a number of naloxonazine-insensitive (non-mu1) ones and may help explain differences in the rate of tolerance development to morphine actions.

References (51)

  • S.C. Roerig et al.

    Brain Res.

    (1987)
  • W.R. Martin et al.

    J. Psychiat Res.

    (1969)
  • M. Wuster et al.

    Biochem Pharmacol.

    (1981)
  • G.W. Pasternak et al.

    Life Sci.

    (1986)
  • P.L. Wood et al.

    Life Sci.

    (1982)
  • R.A. Lutz et al.

    Biochem. Biophys. Res. Comm.

    (1984)
  • L. Toll et al.

    Neuropeptides

    (1984)
  • R.B. Rothman et al.

    Peptides

    (1987)
  • D. Paul et al.

    Eur. J. Pharmacol.

    (1988)
  • D.I. Macht et al.

    J. Am. Pharm. Assoc. Sci. Ed.

    (1931)
  • W.R. Martin et al.

    J. Pharmacol. Exp. Ther.

    (1961)
  • E.L. Way et al.

    J. Pharmacol. Exp. Ther.

    (1969)
  • L. Shuster
  • J.H. Jaffe et al.
  • A.P. Smith et al.
  • H.O.J. Collier

    Nature

    (1965)
  • J. Cochin

    Fed. Proc.

    (1970)
  • M.H. Seevers et al.

    Am. J. Med.

    (1954)
  • J. Cochin et al.

    J. Pharm. Exp. Ther.

    (1964)
  • A. Goldstein et al.
  • W.R. Martin et al.

    J. Pharmacol. Exp. Therap.

    (1976)
  • J.A.H. Lord et al.

    Nature

    (1977)
  • B.L. Wolozin et al.

    Proc. Nat. Acad. Sci. USA

    (1981)
  • R. Schulz et al.

    Mol. Pharmacol.

    (1980)
  • R. Schulz et al.

    J. Pharmacol. Exp. Ther.

    (1981)
  • Cited by (125)

    • Which Opioids Are Safest and Most Effective in Patients With Renal or Hepatic Failure?

      2023, Evidence-Based Practice of Palliative Medicine, Second Edition
    • Opioid-induced bowel disorder and narcotic bowel syndrome

      2023, Handbook of Gastrointestinal Motility and Disorders of Gut-Brain Interactions, Second Edition
    • Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology

      2022, Pharmacology and Therapeutics
      Citation Excerpt :

      Importantly, both in animals and in humans, tolerance does not seem to develop within the GI tract actions of opioids, unlike antinociceptive tolerance, that requires increasing doses of opioids to provide the same level of analgesia (Müller-Lissner et al., 2017; Prichard & Bharucha, 2015). This was first identified in dogs (Plant & Miller, 1926) and has since been replicated across different species (Ling, Paul, Simantov, & Pasternak, 1989; Matsumoto et al., 2016;). Lack of tolerance to morphine-induced constipation has been shown from short (≤72 h) (Ross, Gabra, Dewey, & Akbarali, 2008) to longer (up to 10 days) administration periods.

    • Opioid-induced bowel disorder and narcotic bowel syndrome

      2019, Clinical and Basic Neurogastroenterology and Motility
    View all citing articles on Scopus
    View full text